Tumor necrosis factor alpha (TNF-α) is a cytokine that is released primarily by mononuclear phagocytes in response to immunostimulators. TNF-α is capable of enhancing most cellular processes, such as differentiation, recruitment, proliferation, and proteolytic degradation. At low levels, TNF-α may confer protection against infective agents, tumors, and tissue damage. However, TNF-α also may have a role in many diseases. For example, when administered to mammals or humans, TNF-α causes or aggravates inflammation, fever, cardiovascular effects, hemorrhage, coagulation, and acute phase responses similar to those seen during acute infections and shock states.
Enhanced or unregulated TNF-α production has been implicated in inflammatory diseases, autoimmune diseases and related diseases. Some non-limiting examples of inflammatory and autoimmune diseases include chronic pulmonary inflammatory diseases; dermatitis; psoriasis; systemic lupus erythrematosus; arthritic conditions such as rheumatoid arthritis and osteoarthritis; osteoporosis; Crohn's disease; ulcerative colitis; inflammatory-bowel disease; and multiple sclerosis. Pignet et al., 1990, Nature, 344:245-247, Bissonnette et al., 1989, Inflammation 13:329-339 and Baughman et al., 1990, J. Lab. Clin. Med. 115:36-42 (chronic pulmonary inflammatory diseases); Elliot et al., 1995, Int. J. Pharmac. 17:141-145 (rheumatoid arthritis); von Dullemen et al., 1995, Gastroenterology, 109:129-135 (Crohn's disease).
PDE4 is one of the major phosphodiesterase isoenzymes found in human myeloid and lymphoid lineage cells. The enzyme plays a crucial part in regulating cellular activity by degrading the ubiquitous second messenger cyclic adenosine monophosphate (cAMP) and maintaining it at low intracellular levels. Without being limited by theory, PDE4 inhibitors block the degradation of cAMP via inhibition of the phosphodiesterase type IV (PDE4) enzyme, resulting in an increase in cAMP in PDE4-expressing cells including monocytes, T cells, and neutrophils. Furthermore, the resulted increase in cAMP levels may lead to the modulation of LPS induced cytokines, including inhibition of TNF-α production in monocytes as well as in lymphocytes.
Pharmaceutical compounds that can block the activity or inhibit the production of certain cytokines (e.g., TNF-α) and phosphodiesterase 4 (i.e., PDE4) may be effective in treating, preventing and/or managing inflammatory diseases, autoimmune diseases and related diseases. For example, many small-molecule inhibitors have demonstrated an ability to treat, prevent and/or managing inflammatory diseases implicated by TNF-α (for a review, see Lowe, 1998 Exp. Opin. Ther. Patents 8:1309-1332). However, there are still needs for novel drugs with improved efficacy and/or less side effects for treating inflammatory diseases, autoimmune diseases and related diseases such as dermatomyositis, prurigo nodularis, pyoderma gangrenosum, alopecia areata, hidradenitis suppurtiva, rosacea, lichen planus, giant cell arteritis, Sjogren's syndrome, gout, chronic prostatitis, posterior uveitis, vulvodynia and interstitial cystitis.